Extracellular Matrix Flashcards
What is the extracellular matrix
Complex network of macromolecules (proteins and carbohydrates) deposited by cells which is made up of both fibrillar and non-fibrillar components. After being deposited, it becomes immobilised outside the cells and fills the spaces between the cells
what is fibrillar
fibre -making
what is ECM essential for
development, tissue function and organogenesis
key functions of ECM
- provide physical support
- determine mechanical and physiochemical properties of the tissue
- influence of the growth, adhesion and differentiation status of the cells
what makes up the extracellular matrix in connective tissues
Collagens , Multi-adhesive glycoproteins and proteoglycans
examples of collagens in connective tissue
Type 1, 2,3 (fibrillar) and Type 4 (basement membrane)
examples of multi adhesive glycoproteins present in connective tissue
Laminins(basement membrane), fibronectin and fibrinogen
examples of connective tissues
tendon, bone, cartilage and vitreous humour (jelly that fills eye)
vitreous humour
soft and transparent
tendon and skin
tough and flexible
bone
hard and dense
cartilage
resilient and shock-absorbing
fibrotic disorders occur due to excessive ECM deposition
Liver fibrosis- cirrhosis
Kidney fibrosis or lung fibrosis
disorders due to excessive loss of ECM
osteoarthritis
describe the structure of collagen
made up of 3 alpha chains forming a left handed helix
Structure of Type 1 collagen
made of 2 genes so heterotrimer [α1(I)]2 [α2(I)]
Structure of Types 2 and 3 collagen
homotrimers, having only one chain type. Their compositions are therefore, [α1(II)]3 and [α1(III)]3
Primary sequence of collagen
The primary sequence of collagen proteins contains a characteristic glycine-x-y repeat where x is often proline and y is often hydroxyproline.
To form a stiff triple helical structure, every third position in the must be occupied by the amino acid glycine, as this is the only amino acid small enough to occupy the interior. R region of glycine is H
Hydrogen bond formation between collagen molecules
Hydroxylation of proline contributes to the H bond formation. These provide tensile strength and stability.
Both lysine and hydroxy-lysine residues are involved.
Crosslinking only takes place only after the collagen has been secreted.
how does vitamin C deficiency affect collagen
results in underhydroxylated collagens, with dramatic consequences for tissue stability (scurvy). This is due to the enzymes prolyl hydroxylase and lysyl hydroxylase requiring vitamin C as a co-factor for functionality.
Collagen biosynthesis
Pro alpha chains in ER. Then a series of covalent modifications and folds occur folding the molecule into a triple-helical procollaged. Cleavage of propetide. Collagen. Fibril formation(if appropriate). Cross linking.
Ehlers-Danlos syndrome
a group of inherited connective tissue disorders whose symptoms include stretchy skin and loose joints.
Several of these can arise due to mutations in collagen, which negatively affect collagen production, collagen structure or collagen processing.
Examples of fibril forming collagens
9 and 12
example of non-fibrillar collagen
collagen type IV, which is present in all basement membranes.
In the collagen IV network, the collagen type IV molecules can associate laterally between triple-helical segments as well as head-to head and tail-to tail between the globular domains to give dimers, tetramers and higher order complexes.
What are basement membranes/basal laminae
Basement membranes are flexible, thin mats of ECM surrounding muscle, peripheral nerve and fat cells and most epithelia. Contain collagens, glycoproteins and proteoglycans. eg. basement membrane in kidney
diabetic nehropathy
In the disorder diabetic nephropathy, there is an accumulation of extracellular matrix leading to a highly thickened basement membrane. This restricts renal filtration and can lead to renal failure.
alport syndrome
In Alport syndrome, mutations in collagen IV result in an abnormally split and laminated GBM which is associated with a progressive loss of kidney function and also hearing loss.
how is the extent of stretching of tissues controlled
by weaving collagen and elastic fibres together
what are elastic fibred made of
a core of elastin and microfibrils which are rich in fibrillin
structure of elastin
2 types of segments that alternate along the polypeptide chain: hydrophobic regions, and alpha-helical regions rich in alanine and lysine.
Many lysine side chains are covalently cross-linked.
what is marfans disease
due to disorders in protein fibrillin-2 and has some diverse manifestations involving skeletal, ocular and cardiovascular systems, individuals can be predisposed to aortic ruptures.
2 multi-adhesive glycoproteins
Laminins which are associated with basement membrane and fibronectin
Laminin structure
very large. they are heterortrimeric proteins made up of an α chain, a β chain and a γ chain, which form a cross shaped molecules
muscular dystrophy/epidermolysis bullosa
Inherited diseases. caused froman absence of the α2 chain in laminin 2. Symptoms include hypotonia (abnormally decreased muscle tension), a generalised weakness and deformities of the joints.
fibronectin
found in ECM but also body fluids. can exist as either insoluble fibrillar matric or soluble plasma protein. derived from a single gene, with alternate splicing of mRNAs giving rise to diff types. large molecule and is linked together by disulphide bonds
role of fibronectin
regulate cell adhesion and migration , notably embryogenesis and tissue repair, wound healing (help to promote blood clotting).
proteoglycans
core proteins which are covalently attached to one or more glycosaminoglycan chains (GAG chains)
5 types of proteoglycans
Basement membrane proteoglycans
Aggregating proteoglycans
Small leucine rich proteoglycans
Cell surface proteoglycans
Basement membrane proteoglycan
Perlecan
Aggregating proteoglycan ( which interact with hyaluronan)
Aggrecan
Small leucine-rich proteoglycan
Decorin
Cell surface proteoglycan
Syndecans 1-4
What are GAG chains
Repeating disaccharide units where one of two sugars is amino sugar ( a sugar where the hydroxyl group has been replaced by amine). GAGs can be surface or carboxylate and so carry a high negative charge which attracts Na + ions and water into ECM
Cartilage and GAGS
Cartilage has a matrix rich in collagen with large quantities of GAGs trapped in the mesh work. Balance of swelling pressure is negated by the tension in collagen fibres which generates tensile strength
4 main groups of GAG chains ( based on repeating disaccharide unit)
Hyaluronan, chondroiyin sulfate and Dermatan sulfate, heparin sulfate and keratan sulfate
Hyaluronan
Found in soft connective tissues. Distinct from other GAGs as it is simply a carbohydrate without a core protein . Unsulfated and made up of repeating dissacharidases which can number up to 25,000.
All other GAGs are synthesised and attached to their core protein in the ER and Golgi apparatus inside cells
Highly polymerised and has a high volume
Where can hyularonan be found
Vitreous humour of eye and in sink is, fluid of joints ( here it protects the cartilaginous surface from damage).
Aggrecan
GAGs are highly sulfate which increases negative charge. There are also many negatively charge carboxyl groups and these attract cations like sodium which is osmotically active so a lot of water is drawn in. Water is given up under compressive load- so aggrecan is perfect for cartilage where you need to resist compressive forces
Osteoarthritis
Erosive disease involved in excessive ECM degredation .cushioning of cartilage over ends of bone are lost. With increasing age, aggrecan is cleaved by aggrecanases and metalliproteinases and results in loss of aggrecan fragments to the synovial fluid
